Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease.
Impaired degradation of amyloid beta (Abeta) peptides could lead to Abeta accumulation, an early trigger of Alzheimer's disease (AD). How Abeta-degrading enzymes are regulated remains largely unknown. Cystatin C (CysC, CST3) is an endogenous inhibitor of cysteine proteases, including cathepsin B (CatB), a recently discovered Abeta-degrading enzyme. A CST3 polymorphism is associated with an increased risk of late-onset sporadic AD. Here, we identified CysC as the key inhibitor of CatB-induced Abeta degradation in vivo. Genetic ablation of CST3 in hAPP-J20 mice significantly lowered soluble Abeta levels, the relative abundance of Abeta1-42, and plaque load. CysC removal also attenuated Abeta-associated cognitive deficits and behavioral abnormalities and restored synaptic plasticity in the hippocampus. Importantly, the beneficial effects of CysC reduction were abolished on a CatB null background, providing direct evidence that CysC regulates soluble Abeta and Abeta-associated neuronal deficits through inhibiting CatB-induced Abeta degradation.
Sun
Binggui
B
Gladstone Institute of Neurological Disease, University of California San Francisco, San Francisco, CA 94158, USA.
Zhou
Yungui
Y
Halabisky
Brian
B
Lo
Iris
I
Cho
Seo-Hyun
SH
Mueller-Steiner
Sarah
S
Devidze
Nino
N
Wang
Xin
X
Grubb
Anders
A
Gan
Li
L
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002401:Cathepsin B / Q000378:metabolism*; D055316:Cystatin C / Q000235:genetics* / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics
D016229:Amyloid beta-Peptides; D055316:Cystatin C; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D002401:Cathepsin B